Microwave-assisted wolff rearrangement of cyclic 2-diazo-1,3-diketones: An eco-compatible route to α-carbonylated cycloalkanones

Article abstract of DOI:10.1021/jo8021567

(Chemical Equation Presented) The microwave-assisted Wolff rearrangement of cyclic 2-diazo-1,3-diketones performed in the presence of a stoichiometric amount of alcohol, amine, or thiol is an efficient, user, and environmentally friendly synthetic protocol for the synthesis of α-carbonylated cycloalkanones. This approach proves superior to existing protocols in scope and eco-compatibility.

Full text of DOI:10.1021/jo8021567

SCHEME 1. Synthetic Strategies toward 1
Microwave-Assisted Wolff Rearrangement of
Cyclic 2-Diazo-1,3-Diketones: An Eco-compatible
Route to r-Carbonylated Cycloalkanones
Marc Presset, Yoann Coquerel,* and Jean Rodriguez*
UniVersite´ Paul Ce´zanne, Institut des Sciences Mole´culaires
de Marseille, ISM2 - UMR CNRS 6263, Centre Saint
Je´roˆme, SerVice 531, 13397 Marseille Cedex 20, France
yoann.coquerel@uniV-cezanne.fr;
jean.rodriguez@uniV-cezanne.fr
ReceiVed September 26, 2008
involved.2 The acylation of cycloalkanones (path B) meets the
same disadvantages when a substituent is required on the cycle.2
The transesterification and transamidation strategies (path C)
are quite general but usually require an excess of nucleophile,
an additive, and prolonged reaction times to proceed efficiently.3
However, the methods are not suitable with tertiary alcohols,
poorly nucleophilic amines, or functionalized nucleophiles. The
metal carbenoid insertion in the C-H bond (path D) is
essentially limited to the formation of five-membered rings and
generally proceeds with moderate efficiency with substituted
substrates.4 The ring contraction of cyclic 2-diazo-1,3-diketones
(Wolff rearrangement) followed by trapping of the transient
R-oxoketene5 with a nucleophile is a general method to prepare
substrates of type 1 (path E).6 Although some transition-metal-
catalyzed Wolff rearrangements have been described,7 the
reaction usually occurs at high temperatures or requires some
specific reactors for photoactivation (ultraviolet) or sonication,
precluding the presence of sensitive or reactive functional
groups.
The microwave-assisted Wolff rearrangement of cyclic
2-diazo-1,3-diketones performed in the presence of a sto-
ichiometric amount of alcohol, amine, or thiol is an efficient,
user, and environmentally friendly synthetic protocol for the
synthesis of R-carbonylated cycloalkanones. This approach
provessuperiortoexistingprotocolsinscopeandeco-compatibility.
Simple 1,3-dicarbonyl compounds are exceptional synthetic
platforms due to the presence of four contiguous reaction sites
with alternative nucleophilic and electrophilic character. They
allow a vast array of chemical transformations which can
translate to a fast increase of molecular complexity if they are
judiciously handled. In connection with our program on the
development of Michael-initiated domino and multicomponent
reactions,1 we required an efficient and versatile synthetic access
to a variety of R-carbonylated cycloalkanones of type 1 with
modulated acidity of the activated R proton and a functionalized
Nu group (Scheme 1). Of importance, we required a methodol-
ogy general enough to provide an access to the scarce R-car-
bonylated cyclobutanones. Several reliable strategies are in the
toolbox of the organic chemist for the preparation of 1. All of
them were used in our laboratory in the past decade, and
retrospectively, they all suffer from more or less important
drawbacks. The Dieckmann cyclization (path A) requires a
carefully chosen base and is often associated with reactivity or
regioselectivity problems due to the thermodynamical control
Microwave-assisted organic chemistry (MAOS) is no longer
a laboratory curiosity and will soon be regarded as a common
activation mode of chemical transformations. The synthetic
community starts to realize the true benefits of microwave
activation, and, as a testimony, a number of monographs and
review articles have been made available in the past few years
(2) Benetti, S.; Romagnoli, R.; De Risi, C.; Spalluto, G.; Zanirato, V. Chem.
ReV. 1995, 95, 1065–1114.
(3) For transesterifications, see: (a) Otera, J. Chem. ReV. 1993, 93, 1449–
1470. (b) Mottet, C.; Hamelin, O.; Garavel, G.; Depre´s, J.-P.; Greene, A. E. J.
Org. Chem. 1999, 64, 1380–1382. For transamidations, see: (c) Cossy, J.;
Thelland, A. Synthesis 1989, 753–754. (d) Ponde, D. E.; Deshpande, V. H.;
Bulbule, V. J.; Sudalai, A.; Gajare, A. S. J. Org. Chem. 1998, 63, 1058–1063.
(e) Stefane, B.; Polanc, S. Tetrahedron 2007, 63, 10902–10913.
(4) For a review, see: (a) Adams, J.; Spero, D. M Tetrahedron 1991, 47,
1765–1808. For more recent work, see, for example: (b) Kan, T.; Kawamoto,
Y.; Asakawa, T.; Furuta, T.; Fukuyama, T Org. Lett. 2008, 10, 169–171.
(5) For a review, see: Wentrup, C.; Heilmayer, W.; Kollens, G. Synthesis
1994, 1219–1248.
(1) For recent representative work, see: (a) Lie´by-Muller, F.; Constantieux,
T.; Rodriguez, J. J. Am. Chem. Soc. 2005, 127, 17176–17177. (b) Lie´by-Muller,
F.; Simon, C.; Constantieux, T.; Rodriguez, J. QSAR Comb. Sci. 2006, 25, 432–
438. (c) Coquerel, Y.; Bensa, D.; Doutheau, A.; Rodriguez, J. Org. Lett. 2006,
8, 4819–4822. (d) Coquerel, Y.; Bensa, D.; Moret, V.; Rodriguez, J. Synlett
2006, 2751–2754. (e) Lie´by-Muller, F.; Constantieux, T.; Rodriguez, J. Synlett
2007, 1323–1325. (f) Lie´by-Muller, F.; Allais, C.; Constantieux, T.; Rodriguez,
J. Chem. Commun. 2008, 4207–4209. (g) Coquerel, Y.; Filippini, M.-H.; Bensa,
D.; Rodriguez, J. Chem.sEur. J. 2008, 14, 3078–3092.
(6) For a review, see: Kirmse, W. Eur. J. Org. Chem. 2002, 2193–2256.
(7) For silver-catalyzed rearrangements, see: (a) Sudrik, S.; Sharma, J.;
Chavan, V. B.; Chaki, N. K.; Sonawane, H. R.; Vijayamohanan, K. P Org. Lett.
2006, 8, 1089–1092, and references thereinFor rhodium-catalyzed rearrangements,
see: (b) Lee, Y. R.; Suk, J. Y.; Kim, B. S. Tetrahedron Lett. 1999, 40, 8219–
8221.
10.1021/jo8021567 CCC: $40.75
Published on Web 11/21/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 415–418 415

efficiency through a microwave-assisted Wolff rearrangement
of cyclic 2-diazo-1,3-diketones in the presence a stoichiometric
amount of alcohol, amine, or thiol. The overall eco-compat-
ibility12 of the process is highlighted.
As a test reaction, we submitted a 1:1 mixture of 5,5-
dimethyl-2-diazo-1,3-cyclohexandione (2a) and allyl alcohol
(3a) in toluene to microwave irradiation (300 W) for 3 min in
a sealed tube and were pleased to find that the desired five-
membered ring ꢀ-ketoester 1aa could be obtained with high
purity and almost quantitative yield after simple evaporation
of the solvent (Table 1, entry 1). Stimulated by this result, we
examined the scope of the protocol with several five- to seven-
membered cyclic 2-diazo-1,3-diketones13 and a variety of
nucleophiles (Figure 1). The results are reported in Table 1.
The reactions systematically afforded the pure one-ring-carbon-
contracted products in good to excellent yields and, with a few
exceptions, without need for purification. The reaction virtually
allows the efficient and expeditious synthesis of four- to six-
membered R-carbonylated cycloalkanones with all the nucleo-
philes shown in Figure 1. Indeed, even poorly nucleophilic
alcohols and amines such as phenol (3i, entry 7) and p-
toluenesulfonamide (3t, entry 15) could be used, and the
p-toluenesulfonyl ꢀ-ketoamide 1at would be difficultly available
by other methods.14 Almost no loss of efficiency was observed
with the hindered tertiary alcohols 3g and 3h (entries 6, 19,
28), allowing the straightforward preparation of challenging
substrates such as tert-butyl 2-oxocyclobutanecarboxylate (1dh,
entry 28).15 Although secondary amines 3o-r reacted efficiently
to give the corresponding tertiary amides (entries 10-13 and
26), as expected, total chemoselectivities were observed with
substrates exhibiting two nucleophilic nitrogen atoms such as
3w and 3l (entries 17 and 21). Additionally, thanks to the neutral
reaction conditions, nucleophiles bearing a methyl ester func-
tional group as 3s and 3w (entries 14, 17, and 29) could be
used. Chiral auxiliaries could be easily introduced (entries 16
and 24). This methodology also provided a nice synthetic access
to the valuable product 1ac (entry 3) which was used in the
synthesis of hirsutenes16 and compounds 1bk, 1bl, 1bm, and 1
cm (entries 20-22 and 25) which were recently used in domino
reactions.17
FIGURE 1. Substrates used in the study.
on both the theory and the development of the technique.8 A
microwave effect can be observed in many reactions. Its origin
can be from a purely thermal/kinetic effect according to the
Arrhenius equation as a consequence of the extremely rapid
and internal localized heating of the reaction mixture to a
putative, highly controversial, microwave-specific nonthermal
effect.9 It is, however, universally recognized that polar
substrates and solvents are microwave active, and owing to their
high dipole moments, R-diazo ketones fall into this category.
Indeed, in a couple of recent reports, microwave activation has
been shown to efficiently promote the Wolff rearrangement of
R-diazo ketones in peptide chemistry,10a,b R-diazo sulfoxides,10c
and some microwave specific nonthermal effect has been
suggested.11 Herein, we disclose that a broad range of cyclic
1,3-dicarbonyl compounds of type 1 can be prepared with high
As demonstrated, the scope of the reaction is broad, but one
may also consider the eco-compatibility12 issues of the protocol
in terms of waste, energy, and human resource economy. In
the current era, the efficiency of a chemical process is more
(11) Sudrik, S. G.; Chavan, S. P.; Chandrakumar, K. R. S.; Pal, S.; Date,
S. K.; Chavan, S. P.; Sonawane, H. R. J. Org. Chem. 2002, 67, 1574–1579.
(12) We define eco-compatibility as both economical and ecological compat-
ibility.
(13) 2-Diazo-1,3-diketones were obtained from the corresponding 1,3-
diketones either by treatment with p-toluenesulfonyl azide according to: (a)
Regitz, M.; Hocker, J.; Liedhegener, A. Organic Syntheses; Wiley: New York,
1973; Collect. Vol. V, pp 179-183; or, in a much eco-compatible manner, by
treatment with a polystyrene-supported benzenesulfonyl azide according to: (b)
Green, G. M.; Peet, N. P.; Metz, W. A J. Org. Chem. 2001, 66, 2509–2511.
(14) Following the standard transamidation protocol of ref 3c, treatment of
commercial methyl 2-oxocyclopentanecarboxylate with p-toluenesulfonamide (1
equiv) in the presence of dimethylaminopyridine (DMAP, 1.5 equiv) in refluxing
toluene for 24 h left the starting material unchanged. However, the present
protocol was unsuccessful with the very poorly nucleophilic bis-p-toluene-
sulfonamide (Ts2NH).
(15) Only a few methods are available for the synthesis of tert-butyl
ꢀ-ketoesters: Otera, J.; Yano, T.; Kawabata, A.; Nozaki, H Tetrahedron Lett.
1986, 27, 2383–2386. See also refs 2 and 3a.
(16) Froborg, J.; Magnusson, G. J. Am. Chem. Soc. 1978, 100, 6728–6733.
(17) (a) Pilling, A. W.; Boehmer, J.; Dixon, D. J. Angew. Chem., Int. Ed.
2007, 46, 5428–5430. (b) In this paper, no experimental protocol or characteriza-
tion data are provided for compounds 1bk, 1bl, 1bm, and 1 cm. For a similar
multicomponent approach, see ref 1e.
(8) For recent edited volumes on MAOS, see: (a) MicrowaVe in Organic
Synthesis, 2nd ed.; Loupy, A., Ed.; Wiley-VCH: Weinheim, 2006. (b) Topics in
Current Chemistry, Vol. 266: MicrowaVe Methods in Organic Synthesis; Larhed,
M., Olafsson, K., Eds.; Springer: Berlin/Heidelberg, 2006. For recent representa-
tive reviews on MAOS and its applications, see: (c) Kappe, C. O Chem. Soc.
ReV. 2008, 37, 1127–1139. (d) Coquerel, Y.; Rodriguez, J. Eur. J. Org. Chem.
´
2008, 1125–1132. (e) de la Hoz, A.; D´ıaz-Ortiz, A.; Moreno, A Chem. Soc.
ReV. 2005, 34, 164–178. (f) Hayes, B. L. Aldrichim. Acta 2004, 37 (2), 66–77.
(g) Nu¨chter, M.; Ondruschka, B.; Bonrath, W.; Gum, A Green Chem 2004, 6,
128–141. For recent special issues on MAOS, see: (h) Macromol. Rapid Commun.
2007, 28 (4), 368-513. (i) Tetrahedron 2006, 62 (19), 4635-4732.
(9) Herrero, M. A.; Kremsner, J. M.; Kappe, C. O. J. Org. Chem. 2008, 73,
36–47.
(10) (a) Patil, B. S.; Vasanthakumar, G.-R.; Babu, V. V. S. Lett. Pept. Sci.
2002, 9, 231–233. (b) Kantharaju; Patil, B. S.; Babu, V. V. S Indian J. Chem.
B 2005, 44B, 2611–2613. (c) O’Sullivan, O. C. M.; Collins, S. G.; Maguire,
A. R. Synlett 2008, 659–662.
416 J. Org. Chem. Vol. 74, No. 1, 2009

TABLE 1. Wolff Rearrangement of Cyclic 2-Diazo-1,3-diketones
a All reactions in 10 mL sealed tubes containing 2 mL of dry toluene at a power of 300W with a maximum run time of 3 min. (eventually repeated),
a maximum internal pressure of 17 bar, and a maximal temperature of 180 °C. The microwave irradiation was automatically stopped when one of these
three conditions was met. b Yields are given for the crude clean product obtained by concentration of the reaction mixture followed by high vacuum
removal of all volatiles. c dr ) 1:1. d The crude product was purified by flash chromatography on silica gel.
J. Org. Chem. Vol. 74, No. 1, 2009 417

in a few cases), whereupon the reaction mixture was cooled to 40
°C with an air flow. Concentration of the reaction mixture followed
by high vaccum removal of volatiles afforded the clean crude
product 1 without a need for purification in most cases. For 1aa:
than ever corroborated with its conciseness and its sustainable
aspects. In the synthetic work delineated above, we have placed
a strong emphasis on eco-compatibility12 which resulted in a
protocol where (1) no excess of substrate and no additive is
used, (2) only nitrogen gas is evolved, (3) no purification is
required in most cases, (4) the reaction time is very short, and
(5) the sequence requires a minimum of energy.
In summary, the microwave-assisted Wolff rearrangement of
cyclic 2-diazo-1,3-diketones generates a very reactive ring-
contracted R-oxoketene which can be trapped with a variety of
nucleophiles to give efficiently the corresponding R-carbonylated
cycloalkanones under eco-compatible conditions.
1
96% (117 mg) colorless oil; H NMR (300 MHz, CDCl3) δ 5.87
(tdd, J ) 5.6, 10.4, 17.2 Hz, 1H), 5.34-5.18 (m, 2H), 4.6 (m, 2H),
3.37 (dd, J ) 8.8, 11.1 Hz, 1H), 2.40-2.02 (m, 4H), 1.19 (s, 3H),
1.01 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 211.2 (C), 169.0 (C),
131.6 (CH), 118.3 (CH2), 65.7 (CH2), 54.1 (CH), 52.9 (CH2), 40.7
(CH2), 34.4 (C), 28.8 (CH3), 27.5 (CH3); HRMS (ESI+) [M +
H]+ calcd for C11H17O3 197.1172, found 197.1176.
Acknowledgment. We thank Dr. Jean-Luc Parrain and Pr.
Jean-Marc Pons for their interest in our work, and M.P. thanks
the ENS Cachan for a fellowship award. Financial support from
the French Research Ministry, the Universite´ Paul Ce´zanne, the
CNRS (UMR 6263), and the Conseil Ge´ne´ral des Bouches du
Rhoˆne is also gratefully acknowledged.
Experimental Section
General Procedure. All reactions under microwave irradiation
were performed at 300 W in a CEM Discover 1-300W system
equipped with build-in pressure measurement sensor and a vertically
focused IR sensor (mode discover power time). A solution of
2-diazo-1,3-cycloalkandione 2 (1.0 mmol) and nucleophile 3 (1.0
mmol) in dry toluene (2 mL) in a 10 mL sealed tube equipped
with a Teflon-coated stirring bar was microwave irradiated (ν )
2.45 GHz) at 300 W until the temperature reached 180 °C, or the
pressure reached 17 bar, or for a maximum time of 3 min (repeated
Supporting Information Available: Full characterization
data and copies of 1H and 13C NMR spectra for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO8021567
418 J. Org. Chem. Vol. 74, No. 1, 2009